Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis.
Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis.
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DOI：
10.1136/annrheumdis-2014-205234
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发表时间：
2015-10
影响因子：
27.4
通讯作者：
Tak PP
中科院分区：
文献类型：
--
作者：
Greven DE;Cohen ES;Gerlag DM;Campbell J;Woods J;Davis N;van Nieuwenhuijze A;Lewis A;Heasmen S;McCourt M;Corkill D;Dodd A;Elvin J;Statache G;Wicks IP;Anderson IK;Nash A;Sleeman MA;Tak PP
粒细胞巨噬细胞集落刺激因子（GM-CSF）-GM-CSF受体α轴（GM-CSFRα）可能为类风湿关节炎（RA）的治疗提供新的靶点。因此，我们研究了GM-CSFRα在RA滑膜组织中的细胞表达，并研究了抗GM-CSFR α抗体在RA临床前模型中的体外和体内治疗效果。我们比较了RA或银屑病关节炎（PsA）患者与疾病对照组滑膜活检样本中CD 68或CD 163阳性巨噬细胞的GM-CSFRα表达。此外，我们研究了CAM-3003，一种抗GM-CSFR抗体在DBA/1小鼠的胶原诱导的RA关节炎模型中的作用。CAM-3003的药代动力学特征在未处理的CD 1（ICR）小鼠中进行了研究（见在线补充），并用于解释BALB/c小鼠中药效学研究的结果。GM-CSFRα主要表达于滑膜组织中CD 68和CD 163阳性的巨噬细胞，RA和PsA患者滑膜组织中GM-CSFRα阳性细胞数均显著高于骨关节炎患者和健康对照组。在胶原诱导的关节炎模型中，CAM-3003处理后，临床关节炎评分和发炎滑膜中F4/80阳性巨噬细胞的数量呈剂量依赖性降低。在BALB/c小鼠中，CAM-3003抑制重组GM-CSF介导的外周血单核细胞和中性粒细胞的边集。这些发现支持正在进行的旨在干扰GM-CSF或其受体在各种形式的关节炎，如RA和PsA的治疗。
Previous work has suggested that the granulocyte macrophage colony stimulating factor (GM-CSF)–GM-CSF receptor α axis (GM-CSFRα) may provide a new therapeutic target for the treatment of rheumatoid arthritis (RA). Therefore, we investigated the cellular expression of GM-CSFRα in RA synovial tissue and investigated the effects of anti-GM-CSFRα antibody treatment in vitro and in vivo in a preclinical model of RA. We compared GM-CSFRα expression on macrophages positive for CD68 or CD163 on synovial biopsy samples from patients with RA or psoriatic arthritis (PsA) to disease controls. In addition, we studied the effects of CAM-3003, an anti-GM-CSFR antibody in a collagen induced arthritis model of RA in DBA/1 mice. The pharmacokinetic profile of CAM-3003 was studied in naïve CD1(ICR) mice (see online supplement) and used to interpret the results of the pharmacodynamic studies in BALB/c mice. GM-CSFRα was expressed by CD68 positive and CD163 positive macrophages in the synovium, and there was a significant increase in GM-CSFRα positive cells in patients in patients with RA as well as patients with PsA compared with patients with osteoarthritis and healthy controls. In the collagen induced arthritis model there was a dose dependent reduction of clinical arthritis scores and the number of F4/80 positive macrophages in the inflamed synovium after CAM-3003 treatment. In BALB/c mice CAM-3003 inhibited recombinant GM-CSF mediated margination of peripheral blood monocytes and neutrophils. The findings support the ongoing development of therapies aimed at interfering with GM-CSF or its receptor in various forms of arthritis, such as RA and PsA.